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Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome.

ABSTRACT: We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel+/- mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior-posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel+/-. In the additional 22q11.2-related genotypes: Tbx1+/-, Ranbp1-/-, Ranbp1+/- and LgDel+/-:Raldh2+/-; axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.

SUBMITTER: Motahari Z

PROVIDER: S-EPMC7645708 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome.

Motahari Zahra Z Maynard Thomas M TM Popratiloff Anastas A Moody Sally A SA LaMantia Anthony-S AS

Human molecular genetics 20201101 18

We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel+/- mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify ph ...[more]

PMID: 32901287

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Project description:Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we explored the influence of olfactory and trigeminal signaling in the nasal cavity. A forced choice water consumption paradigm was used to ascertain whether trigeminal and olfactory stimuli could influence behaviour in mice. Mice avoided water sources surrounded by both volatile TRPV1 (cyclohexanone) and TRPA1 (allyl isothiocyanate) irritants and the aversion to cyclohexanone was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioural effect we recorded from single trigeminal sensory axons innervating the nasal respiratory and olfactory epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in mice expressing channel-rhodopsin (ChR2) under the olfactory marker protein (OMP) promoter. Photoactivation of olfactory sensory neurons produced no modulation of axonal action potential conduction in individual trigeminal axons. Similarly, no evidence was found for collateral branching of trigeminal axon that might serve as a conduit for cross-talk between the olfactory and respiratory epithelium and olfactory dura mater. Using direct assessment of action potential activity in trigeminal axons we observed neither paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the rodent nasal cavity. Our current results suggest that olfactory sensory neurons exert minimal influence on trigeminal signals within the nasal cavity.

Project description:Purpose: The cellular composition of the trigeminal ganglion is altered in the mouse model of 22q11.2 deletion syndrome (the LgDel mouse). The goal of this study is to use RNA-seq to identify transcriptional differences in the embryonic day 10.5 trigeminal ganglion that prefigure changes in mature cell identity in this cranial nerve ganglion. Methods: Trigeminal ganglion mRNA profiles of E10.5 trigeminal ganglia from WT and LgDel mice were generated by deep sequencing. Ganglia samples were prepared as pools of at least 6 ganglia each, from at least 3 embryos. 5 biological replicates of LgDel and WT pools were sequenced. Paired-end libraries were constructed according to the Illumina protocol for the HiSeq2000 platform. Each pooled CNgV RNA sample, defined as a single biological replicate, was fragmented prior to cDNA conversion to ensure transcript coverage. WT (n = 5 replicates) and LgDel (n = 5 replicates) were subjected to sequencing (~100 million paired-end reads/replicate, 100 bp read length) on the Illumina HiSeq2000 platform. Quality-filtered reads were aligned against the mouse reference genome (GRCm38/mm10) using HISAT2 (v.2.1.0). These alignments were indexed using SAMtools (v.1.4) and aligned reads assembled into transcripts using Cufflinks (v.2.2.1) (58). Differential expression analysis was performed using Cufflinks. Validation of key transcriptional differences was performed by SYBR Green qPCR. Results: For WT RNA-Seq, 111–123 million paired-end reads were generated after QC filtering, and 97.3–97.9% of the reads aligned to the mouse genome reference sequence. For LgDel RNA-Seq, 77–137 million paired-end reads were generated after QC filtering, and 94.3–97.8% of the reads aligned to the mouse genome reference sequence. LgDel versus wild-type (WT) CNgV transcriptomes differ significantly at E10.5 just after the ganglion has coalesced. Some changes parallel altered proportions of cranial placode versus cranial neural crest-derived CNgV cells. Others are consistent with a shift in anterior–posterior patterning associated with divergent LgDel cranial nerve differentiation. The most robust quantitative distinction, however, is statistically verifiable increased variability of expression levels for most of the over 17 000 genes expressed in common in LgDel versus WT CNgV. Conclusions: Quantitative expression changes of functionally relevant genes and increased stochastic variation across the entire CNgV transcriptome at the onset of CN V differentiation prefigure subsequent disruption of cranial nerve differentiation and oropharyngeal function in LgDel mice.

Dataset Information

Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome.

Publications

Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome.

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